HMG-CoA reductase inhibitors represent a new class of cholesterol lowering drugs. Relatively low levels of these drugs effectively reduce plasma cholesterol levels. These drugs are believed to function by inhibiting the chemical transformation HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
In general there have been very few clinical problems with the use of the HMG reductase inhibitors. The most serious reported adverse effects of lovastatin, a commercially available HMG-CoA reductase inhibitor, are myopathy and asymptomatic but marked and persistent increases in liver transaminases. A method of treating HMG-CoA reductase inhibitor-associated myopathy is discussed in copending patent application Ser. No. 298,535 filed, Jan. 18, 1989. About 1.9% of the patients treated with lovastatin in clinical trials have had asymptomatic but marked and persistent transaminase increases, particularly serum glutamic pyruvic transaminase, J. A. Tobert, Am J. Cardiol., 1988, 62: 28J-34J. The elevated transaminase level is reversible upon discontinuance of the therapy.
A branch of the mevalonate cholesterol biosynthetic pathway in mammalian cells leads to the formation of Coenzyme Q.sub.10 [reviewed by Brown and Goldstein, J. Lipid Res., 21 505 1980]. Coenzyme Q.sub.10 (2,3-dimethoxy-5-methyl-6-decaprenyl-1, 4-benzoquinone) is a redox component in the respiratory chain and is found in all cells having mitochondria. It is thus an essential co-factor in the generation of metabolic energy and may be important in liver function. J. S. MacDonald et al. have reported (Am. J. Cardiol 1988; 62 6J-27J) that co-administration of mevalonate, with lovastatin in rabbits, rats and dogs, prevents the increases in transaminase levels. This result demonstrates that the transaminase increase produced by lovastatin and other HMG-CoA reductase inhibitors is a direct consequence of inhibition of mevalonate synthesis.
Although cholesterol-lowering therapy through the use of HMG-CoA reductase inhibitors is generally free of side reactions, it would be of considerable benefit to counteract the increased transaminase levels observed in a small number of patients.